Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C1326912 (tumorigenesis)
 57,481 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiogenesis, or the formation of new blood vessels, is a dynamic process needed for embryogenesis, post-natal growth, morphogenesis, tumorigenesis, and for other biological processes. Angiogenesis is very important for tumor development and progression. This review examines the activators and inhibitors of angiogenesis with emphasis on the pituitary gland and pituitary neoplasms. Some of the proteins regulating angiogenesis in pituitary tumors such as vascular endothelial growth factor (VEGF) and VEGF receptors, fibroblasts growth factors (FGF), transforming growth factor beta (TGFB), interleukins, interferons, and matrix metalloproteinases (MMPs) and inhibitors of MMPs have been examined in animal and human pituitary tumor models. However, many other significant regulators of angiogenesis including angiopoietins, angiostatin, and thrombospondins have not been studied extensively in pituitary tumors to date. Newer concepts and developments in angiogenesis such as vasculogenic mimicry and gene therapy approaches to angiogenesis in cancer treatment are also discussed.
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PMID:Angiogenesis in normal and neoplastic pituitary tissues. 1253 79

OBJECTIVE: To study the expression of vascular endothelial growth factor (VEGF) mRNA isoforms in ovarian carcinoma and to explore their role in tumorigenesis and development of ovarian carcinoma. METHODS: The types and levels of VEGF mRNA isoforms of surgical samples from 30 patients with ovarian carcinoma were determined by relatively quantative RT-PCR, nest PCR and sequence analysis. RESULTS: VEGF(121), VEGF(145), VEGF(165) and VEGF(189)mRNA were detected in normal ovaries and ovarian carcinoma tissues. The expression level of VEGF(121) was significantly higher than that of VEGF(145), VEGF(165) and VEGF(189) (P<0.001, respectively). The expression of all 4 isoforms in carcinoma tissues was increased significantly compared with that in normal ovaries (P<0.05). CONCLUSION: Overexpression of VEGF(121), VEGF(145), VEGF (165) and VEGF(189) mRNA, especially VEGF(121), was found in varian carcinoma tissues. This findings suggest that all 4 VEGF isoforms may be involved in the tumorigenesis and development of ovarian carcinoma and VEGF(121) may play a key role.
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PMID:[Expression of mRNA isoforms of vascular endothelial growth factor in ovarian carcinoma] 1255 24

Angiogenesis, a process related to tumor growth and malignancy, is stimulated by several growth factors. Among these is vascular endothelial growth factor (VEGF), which acts on endothelial cells by binding with 2 specific receptors, VEGFR1 and VEGFR2. Recent studies have demonstrated that VEGF expression is correlated with microvessel density (MVD) and tumor progression. Digestive endocrine tumors are heterogeneous neoplasms exhibiting variable biological aggressiveness and behavior that often are not predictable on morphologic grounds alone. The aims of this study were to evaluate the expression of VEGF, VEGFR1, and VEGFR2 in digestive endocrine tumors and to examine its correlation with MVD and malignancy. A total of 84 specimens from endocrine neoplasms and normal gut and pancreatic tissue were immunohistochemically studied using specific antibodies directed against VEGF, VEGFR1, VEGFR2, endothelial antigens, and gastroenteropancreatic hormones. Ultrastructural immunocytochemistry was performed to identify the cellular localization of VEGF and the VEGFRs. In normal tissues, VEGF immunoreactivity was detected in G cells and PP cells. Ultrastructurally, VEGF was localized within secretory granules. The VEGFRs were not significantly expressed by normal endocrine cells. VEGF-immunoreactive (IR) cells were detected in 40 of 83 tumors, mainly G cell and enterochromaffin cell neoplasms. VEGFR1-IR cells were found in 44 of 82 tumors, and VEGFR2-IR cells were found in 55 of 82 tumors, with no predilection for any specific tumor type. The expression of VEGF and its receptors did not correlate with MVD or malignancy. These results suggest that in normal tissues, endothelial functions may be regulated by VEGF produced by some endocrine cells and that a VEGF/VEGFR binding mechanism may be involved in tumorigenesis, but not in tumor progression and aggressiveness.
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PMID:Localization of vascular endothelial growth factor and its receptors in digestive endocrine tumors: correlation with microvessel density and clinicopathologic features. 1260 62

We have demonstrated that nuclear factor-kappa B (NF-kappa B) is constitutively activated in human pancreatic adenocarcinoma and human pancreatic cancer cell lines but not in normal pancreatic tissues or in immortalized, nontumorigenic pancreatic epithelial cells, suggesting that NF-kappa B plays a critical role in the development of pancreatic adenocarcinoma. To elucidate the role of constitutive NF-kappa B activity in human pancreatic cancer cells, we generated pancreatic tumor cell lines that express a phosphorylation defective I kappa B alpha (S32, 36A) (I kappa B alpha M) that blocks NF-kappa B activity. In this study, we showed that inhibiting constitutive NF-kappa B activity by expressing I kappa B alpha M suppressed the tumorigenicity of a nonmetastatic human pancreatic cancer cell line, PANC-1, in an orthotopic nude mouse model. Immunohistochemical analysis showed that PANC-1-derived tumors expressed vascular endothelial growth factor (VEGF) and induced angiogenesis. Inhibiting NF-kappa B signaling by expressing I kappa B alpha M significantly reduced expression of Bcl-x(L) and Bcl-2. The cytokine-induced expression of VEGF and Interleukin-8 in PANC-1 cells is also decreased. Taken together, these results suggest that the inhibition of NF-kappa B signaling can suppress tumorigenesis of pancreatic cancer cells and that the NF-kappa B signaling pathway is a potential target for anticancer agents.
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PMID:Inhibition of constitutive NF-kappa B activity by I kappa B alpha M suppresses tumorigenesis. 1261 62

Interleukin-6 (IL-6) has received particular attention in the pathogenesis of cervical cancer, although the underlying mechanism remains elusive. This study revealed that IL-6 promotes in vivo tumor growth of human cervical cancer C33A cells, but does not substantially alter their in vitro growth kinetics. The in vivo angiogenic assays showed that IL-6 increases angiogenic activity in human cervical cancer cells, an effect that is specifically associated with upregulation of vascular endothelial growth factor (VEGF). Also, using anti-VEGF antibody to block VEGF function significantly inhibited IL-6-mediated angiogenesis and tumor growth in nude mice, strongly supporting the critical role of VEGF in the IL-6-mediated cervical tumorigenesis. Accordingly, the signaling pathway downstream of IL-6/IL-6R responsible for the regulation of VEGF was investigated. Notably, pharmacological inhibition of PI3-K or MAPK failed to inhibit IL-6-mediated transcriptional upregulation of VEGF. Meanwhile, blocking STAT3 pathway with dominant-negative mutant STAT3D effectively abolished IL-6-induced VEGF mRNA. In transient transfections, a luciferase reporter construct containing the full-length 1.5-kb VEGF promoter or a 1.2-kb fragment lacking the known hypoxic-response element also exhibited the same degree of response to IL-6. Additionally, transient transfection of STAT3D downregulated the 1.2-kb VEGF promoter luciferase reporter stimulated by IL-6. Based on the above phenomenon combined with the concomitant increased tumor expression of IL-6 and VEGF in cervical cancer tissues, we conclude that IL-6 may promote cervical tumorigenesis by activating VEGF-mediated angiogenesis via a STAT3 pathway.
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PMID:Interleukin-6 promotes cervical tumor growth by VEGF-dependent angiogenesis via a STAT3 pathway. 1262 15

Lysophosphatidic acid (LPA) receptors including LPA(1), LPA(2), and LPA(3) mediate lysophosphatidic acid signals. We analyzed the expression of LPA receptors, vascular endothelial growth factor (VEGF), and interleukin-8 in 97 patients from normal ovary to ovarian cancer, using reverse transcription polymerase chain reaction. LPA(2), LPA(3), and VEGF expression ratios significantly increased in cancer, compared to those in non-cancerous state (P<0.05). A significant correlation in the expression ratios between LPA(2) or LPA(3) and VEGF was found (gamma=0.617, P<0.0001; gamma=0.431, P<0.001) in patients with cancer. These results suggested that LPA(2) and LPA(3) may be involved in VEGF expression mediated by LPA signals in human ovarian oncogenesis.
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PMID:Expression of lysophosphatidic acid receptors and vascular endothelial growth factor mediating lysophosphatidic acid in the development of human ovarian cancer. 1266 80

We have previously shown in an in vitro wounding system of cultured endothelial cells (EC) that vascular endothelial growth factor (VEGF(165)) treatment upregulated the level of factor VIII (FVIII) in the cells facing an experimental wound. The FVIII upregulation induced by VEGF(165) could be abolished by rhuMab VEGF, a humanized antibody that blocks VEGF functions and inhibits tumorigenesis. Because the thrombotic system is actively involved in angiogenesis, we further investigated the effects of rhuMab VEGF on the regulation of FVIII. Although non-disturbed cells distant from a wound were not affected by rhuMab VEGF treatment, FVIII was also significantly upregulated in the cells along the wound in cultures treated with the antibody alone. RhuMab VEGF stimulation of FVIII could be blocked by VEGF(165). When cells were treated with rhuMab VEGF and VEGF(165) combined together, the stimulation or inhibition of FVIII expression was dose-related and dependent on the amount of excess free rhuMab VEGF and rhuMab VEGF:VEGF(165) immune complexes. Thus, both VEGF(165) and rhuMab VEGF used as single reagents enhanced FVIII in activated endothelial cells, while the immune complexes suppressed the upregulation. Following rhuMab VEGF treatment, two distinct activated endothelial subpopulations that differ in their ability to internalize rhuMab VEGF and express interleukin-1 (IL-1) were identified. IL-1beta but not IL-1alpha appeared to be acting as a mediator between the two endothelial subpopulations as the FVIII upregulation induced by rhuMab VEGF could be totally abolished by treatment with type II soluble IL-1 receptor (sIL-1RII).
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PMID:An antibody to VEGF upregulates factor VIII via interleukin-1 in activated adrenal cortex-derived capillary endothelial cells. 1268 55

Human high-grade astrocytomas (HGA) are the most prevalent incurable brain tumors. We found that the vast majority of HGA patients overexpress a restricted receptor for an immune regulatory cytokine, interleukin 13 (IL-13). Interestingly, the HGA-associated restricted receptor protein IL-13Ralpha2 is expressed in the testes, and its gene is localized to chromosome X. These mirror the expression pattern and genomic localization of cancer/testes tumor antigens (CTA). Hypothetical considerations and now experimental evidence are beginning to point towards epigenetics, and DNA methylation alterations in particular, as being responsible for the appearance in cancer of CTA, including IL-13Ralpha2. In line with our interest in the X chromosome and oncogenesis, we have identified a new ubiquitous angiogenic factor in HGA, a vascular endothelial growth factor-D (VEGF-D). We have also demonstrated that the activating protein-1 (AP-1) family of transcription factors play a potentially critical role in the progression of gliomas by eliciting uncontrolled upregulation of VEGF-D and other compounds essential for cancer cell proliferation, tumorigenesis, and infiltration. The possibility exists that an unopposed constitutive increase in AP-1 activity in HGA is related to epigenetic silencing of the inhibitors of AP-1 activity. These phenomena offer potential targets for exploitation in either prevention or early detection of brain tumors. For example, anticancer vaccines against shared CTA could help in prevention of HGA development. Furthermore, drugs with anti-AP-1 activity could be effective in preventing formation/progression of HGA, or progression from less malignant lower grade gliomas to HGA. Also, circulating antibodies against CTA and factors that are AP-1 regulated may provide a useful tool in early detection of brain tumors or for monitoring their progression following initial treatment.
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PMID:Epigenetics in high-grade astrocytomas: opportunities for prevention and detection of brain tumors. 1272 28

Tumor angiogenesis is governed by a complex balance of positive and negative angiogenic factors. Development of chemically-induced mouse skin tumors appears to be highly dependent on an early burst of neovascularization. We have previously shown that Ha-ras-driven vascular endothelial growth factor (VEGF) expression plays a pivotal role in this process. However, the status of other critical positive and negative angiogenic factors throughout skin tumorigenesis has not been studied to the same extent. In the present study, we show that another VEGF family member, placenta growth factor (PlGF), was highly upregulated at all tumor stages in a ras-dependent manner. The study of angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2), ligands of receptor tyrosine kinase 2 (Tie-2), showed that while stroma-derived Ang-2 was increased, epidermal Ang-1 expression was completely abolished at early papilloma formation. Studies using epidermal tumor cell lines suggest that the disappearance of Ang-1 also depends on ras activation, extending the plethora of events controlled by this oncogene in mouse skin carcinogenesis. Our results indicated that tumor development occurred in a strong angiogenesis-prone scenario in which PlGF and Ang-2 acted cooperatively with VEGF, whereas the negative or stabilizing effect of Ang-1 was abrogated. A time-course sequence of expression of angiogenic factors expressed throughout tumor growth, as well as the identification of key signaling molecules triggering the angiogenic response, may contribute to the development and testing of antiangiogenic therapeutic strategies with this in vivo tumor model.
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PMID:Modulation of the angiogenesis response through Ha-ras control, placenta growth factor, and angiopoietin expression in mouse skin carcinogenesis. 1276 7

A metastatic renal cell carcinoma (RCC) tumor model xenograft that expresses the targetable, membrane-bound tumor-associated antigen carbonic anhydrase type 9 (CA IX) is described. The xenograft, established from a high-grade type-2 chromophil RCC (cRCC), has been serially transplanted in immune compromised mice, in which it grows orthotopically under the renal capsule, doubling its size every 9 weeks and sending metastases to the lung and liver at approximately 20 weeks. Tumors were capable of being imaged using a micro-PET (micro-positron emission tomograph) with an 18-fluorodeoxyglucose (18-FDG) tracer. Subsequent xenograft generations have conserved immunohistochemical and ultrastructural properties typical for malignant renal epithelium-derived neoplasia (vimentin+, CK-19+, CA IX+ with hypoxia-inducible factor (HIF)-1 alpha constitutive expression) and have demonstrated extensive proliferation, lack of apoptosis, severe genetic alterations, and molecular expression alterations; transforming growth factor beta 1 (TGF-beta 1), hepatocyte growth factor (HGF), proto-oncogene (c-met), matrix metalloproteinase (MMP)-1, and vascular endothelial growth factor (VEGF) C and D were overexpressed, whereas human epidermal growth factor receptor (HER)-2, MMP-2 and MMP-9, VEGF-R3, p53, and p27 were severely down-regulated, suggesting a proangiogenic environment, local invasiveness, and facilitated lymphatic metastasis. Altogether, LABAZ1 provides a relevant and flexible model to study the biology of cRCC, the role of CA IX in RCC tumorigenesis, progression, and metastasis, and a platform for testing new targeted therapeutic strategies.
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PMID:LABAZ1: A metastatic tumor model for renal cell carcinoma expressing the carbonic anhydrase type 9 tumor antigen. 1294 20


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